Generation and characterization of preclinical models to study premature aging and cardiovascular disease in Hutchinson-Gilford progeria syndrome

Resumo

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by the expression of a mutant form of the nuclear protein lamin A called progerin, which is produced as the result of a de novo point mutation in the LMNA gene. Patients look healthy at birth, and symptoms typically emerge from the first year of life. Children exhibit accelerated ageing and severe cardiovascular alterations, which reduce their life expectancy to 14.6 years. Although progeria patients also show extreme lipodystrophy, its causal role in HGPS-associated cardiovascular pathology and reduced lifespan remains largely unexplored. Currently there is no cure for HGPS and therefore it is urgent to understand HGPS-associated molecular, cellular, and functional alterations to identify new therapeutic targets and develop novel treatments. Because patients are diagnosed when symptoms are already present, it is key to assess the reversibility of progerin-induced tissue damage and to establish the optimal time window for treatments. Moreover, studying the relative contribution of specific cell types would facilitate the development of more efficient and safer therapies. In order to address these questions, in this Doctoral Thesis we used the HGPSrev HGPS mouse model, which ubiquitously expresses progerin and lacks lamin A and allows to eliminate progerin and concomitantly restore lamin A expression in a time- and cell type-specific manner. We crossed HGPSrev mice with adequate Cre transgenic lines to assess the effects of suppressing progerin ubiquitously at different disease stages (HGPSrev-Ubc-CreERT2), or specifically in different cell types, namely vascular smooth muscle cells (VSMCs) and cardiomyocytes (HGPSrev-SM22αCre) or adipocytes (HGPSrev-FABP4Cre). We found ubiquitous progerin suppression significantly extended lifespan when induced in mildly symptomatic mice. Remarkably, progerin suppression restricted to VSMCs and cardiomyocytes prevented vascular alterations and normalised lifespan. Moreover, progerin suppression in adipocytes partially prevented fat loss and adipocyte morphological alterations and ameliorated vascular alterations and increased lifespan. Mechanistically, high-throughput transcriptomic and metabolomic studies showed that progerin suppression in adipocytes tended to normalise gene expression in different fat depots and in aorta, and partially prevented the systemic imbalance of arachidonic acid-derived metabolites in progeroid mice. Transplantation of wild-type adipose tissue into HGPSrev mice ameliorated body weight loss and extended maximal lifespan. Collectively, our findings establish a link among HGPS-associated lipodystrophy, vascular alterations, and reduced lifespan, and open new avenues for the development of innovative therapies targeting vascular cells and adipose tissue for more effective treatment of HGPS